Popular drug faces resistance in a common fungal pathogen

Resistance has taken another victim, this time one of the world’s most common antifungal medications used to treat upper-respiratory illness and air-born allergens.

The drugs, called triazoles, have been shown to be ineffective against a common fungal pathogen called Aspergillus fumigatus in several parts of India. Researchers have determined that the most likely cause for the origin and spread of the resistance is the heavy application of agricultural fungicides.

"Our paper describes the finding of a multi-drug resistant genotype in a very common fungal pathogen Aspergillus fumigatus, a genotype that is found in many regions in India, in both natural environments and in clinics and patients," says Xu. "Our analyses suggest that the genotype likely originated from a cross between a foreign strain and a native strain in India and that its wide distribution was due to the selective pressure posed by the heavy application of agricultural fungicides in India. It's the first robust evidence that agricultural fungicide use can severely impact human fungal disease management."

Aspergillus fumigatus is prevalent in all parts of the world, Xu explains, adding it is among the most common indoor and outdoor molds. "One of the things that distinguishes this mold from most other fungi is that it can grow at a very high temperature including in the middle of a compost."

It is also the most common opportunistic pathogen affecting the upper respiratory tract, he adds. In fact, every individual inhales several hundred thousand spores of the pathogen each day. And while healthy individuals are able to easily expel it by coughing or sneezing, for those who are immunocompromized, such as those with AIDS or leukemia, the organism can be invasive, difficult to treat and can result in high mortality rates.

The original discovery of azole resistance in this organism was made a few years ago by Xu’s colleague Anuradha Chowdhary, a professor in the Department of Medical Mycology at the Vallabhbhai Patel Chest Institute at the University of Delhi, who had been treating a patient with a triazole drug and found a multi-drug resistant strain existed in the patient and was affecting treatment.

Chowdhary and colleagues subsequently monitored the prevalence of this multi-drug resistant genotype and sampled soil from different environments. They also collected information from patients being treated by the triazole line of drugs and isolated a number of strains of the species and found these strains showed cross-resistance to fungicides used extensively in agriculture.

The researchers also compared A. fumigatus from India with those from other countries, including the Netherlands, France, Germany and China, to determine if the genotype existed in other countries and if so, whether they had the same level of resistance. Surprisingly, says Xu, they did not. "We didn’t expect this," he says. "When we compared the genotype from India to the resistant strains outside of India we found that the Indian resistant genotype was unique. Furthermore, it was not due to a single mutation from an existing susceptible strain from within India or any strain from outside of India but it was likely a recombinant between a resistant genotype from outside of India and a susceptible native genotype."

The researchers will continue to study more strains in India and other countries to get a deeper understanding of the origin and mechanism of Triazole resistance on a global scale.

Xu is concerned about the implications of this finding. "This resistance could be a growing public health problem," he says. "A. fumigatus can produce a lot of spores in a very short time and the spores can disperse very rapidly through the air, as shown in the case within India. Furthermore, the azole drugs are the most commonly used to treat infections caused by this and many other fungi. The effectiveness of these drugs on treating A. fumigatus infections in other parts of the world could be in jeopardy in the near future."